The therapeutical efficacies of eleven oxime-based acetylcholinesterase reactivators were compared in an in vivo (rat model) study of treatment of intoxication caused by tabun. In this group there were some currently available oximes (obidoxime, trimedoxime and HI-6) and the rest were newly synthesized compounds. The best reactivation efficacy for acetylcholinesterase in blood (expressed as percent of reactivation) among the currently available oximes was observed after administration of trimedoxime (16%) and of the newly synthesized K127 (22432) (25%). The reactivation of butyrylcholinesterase in plasma was also studied; the best reactivators were trimedoxime, K117 (22435), and K127 (22432), with overall reactivation efficacies of approximately 30%. Partial protection of brain ChE against tabun inhibition was observed after administration of trimedoxime (acetylcholinesterase 20%; butyrylcholinesterase 30%) and obidoxime (acetylcholinesterase 12%; butyrylcholinesterase 16%).

Center of Advanced Studies Faculty of Military Health Sciences Hradec Kralove Czech Republic

Department of Toxicology Faculty of Military Health Sciences Trebesska 1575 500 01 Hradec Kralove Czech Republic

Medicinal Science Division Korea Research Institute of Chemical Technology PO Box 107 Yusong Taejon 305 606 Korea

Zobrazit více v PubMed

Bajgar J. Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis and treatment. Adv. Clin. Chem. 2004;38:151–216. PubMed

Marrs T. C. Organophosphate poisoning. Pharmacol. Ther. 1993;58:51–66. PubMed

Dawson R. M. Review of oximes available for treatment of nerve agent poisoning. J. Appl. Toxicol. 1994;14:317–331. PubMed

Koplovitz I, Steward JR. A comparison of the efficacy of HI6 and 2-PAM against soman, tabun, sarin, and VX in the rabbit. Toxicol. Lett. 1994;70:269–279. PubMed

Kuca K, Jun D, Bajgar J. Currently used cholinesterase reactivators against nerve agent intoxication: comparison of their effectivity in vitro. Drug Chem. Toxicol. 2007;30:31–40. PubMed

Wilson IB, Sondheimer F. A specific antidote against lethal alkyl phosphate intoxication. V. Antidotal properties. Arch. Biochem. Biophys. 1957;69:468–474. PubMed

Musilek K, Lipka L, Racakova V, Kuca K, Jun D, Dohnal V, Dolezal M. New methods in synthesis of acetylcholinesterase reactivators and evaluation of their potency to reactivate cyclosarin-inhibited AChE. Chem. Papers. 2006;60:48–51.

Musilek K, Kuca K, Jun D, Dohnal V, Kim TH, Jung YS, Dolezal M. Synthesis of reactivators of phosphorylated acetylcholinesterase of bis-pyridiniumdialdoxime type with a 3-oxapentane connecting chain and their testing in vitro on a model of the enzyme inhibited by chlorpyrifos and methylchlorpyrifos. Ces. Slov. Farm. 2006;15:115–119. PubMed

Musilek K, Holas O, Jun D, Dohnal V, Gunn-Moore F, Opletalova V, Dolezal M, Kuca K. Monooxime reactivators of acetylcholinesterase with (E)-but-2-ene linker: Preparation and reactivation of tabun- and paraoxon-inhibited acetylcholinesterase. Bioorg. Med. Chem. 2007;15:6733–6741. PubMed

Musilek K, Holas O, Kuca K, Jun D, Dohnal V, Opletalova V, Dolezal M. Synthesis of monooxime-monocarbamoyl bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against tabun- and paraoxon-inhibited acetylcholinesterase. J. Enzym. Inhib. Med. Chem. 2008;23:70–76. PubMed

Musilek K, Kucera J, Jun D, Dohnal V, Opletalova V, Kuca K. Monoquaternary pyridinium salts with modified side chain-synthesis and evaluation on model of tabun- and paraoxon-inhibited acetylcholinesterase. Bioorg Med Chem. 2008;16:8218–8223. PubMed

Kim TH, Kuca K, Jun D, Jung YS. Design and synthesis of new bis-pyridinium oxime reactivators for acetylcholinesterase inhibited by organophosphorous nerve agent. Bioorg. Med. Chem. Lett. 2005;15:2914–2917. PubMed

Kuca K, Jun D, Kim TH, Cabal J, Jung YS. In vitro evaluation of new acetylcholinesterase reactivators as causal antidotes against tabun and cyclosarin. Bull. Kor. Chem. Soc. 2006;27:395–398.

Shih TM. Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats. Arch. Toxicol. 1993;67:637–646. PubMed

Bieger D, Wasserman O. Ionization constants of cholinesterase-reactivating bis-pyridinium aldoximes. J. Pharm. Pharmacol. 1967;19:844–847. PubMed

Kuca K, Jun D, Musilek K. Structural requirements of acetylcholinesterase reactivators. Mini Rev. Med. Chem. 2006;6:269–277. PubMed

Cabal J, Kuca K, Kassa K. Specification of the structure of oximes able to reactivate tabun inhibited acetylcholinesterase. Pharmacol. Toxicol. 2004;95:81–86. PubMed

Kassa J, Cabal J. A comparison of the efficacy of a new asymmetric bispyridium oxime BI–6 with currently available oximes and H oximes against soman by in vitro and in vivo methods. Toxicology. 1999;132:111–118. PubMed

Kassa J, Jun D, Karasova J, Bajgar J, Kuca K. A comparison of reactivating efficacy of newly developed oximes (K 074, K 075) and currently available oximes (obidoxime, HI–6) in soman, cyclosarin and tabun-poisoned rats. Chem. Biol. Interact. 2008;175:425–427. PubMed

Lorke DE, Hasan MY, Nurulain SM, Shafiullah M, Nagelkerke N, Petroianu GA. Effect of intrathecal pralidoxime administration upon survival of rats exposed to the organophosphate paraoxon. Neurotoxicology. 2008;29:663–670. PubMed

Lorke DE, Kalasz H, Petroianu GA, Tekes K. Entry of oximes into the brain: a review. Curr. Med. Chem. 2008;15:743–753. PubMed

Gyenge M, Kalász H, Petroianu GA, Laufer R, Kuca K, Tekes K. Measurement of K–27, an oxime-type cholinesterase reactivator by high-performance liquid chromatography with electrochemical detection from different biological samples. J. Chromatogr. A. 2007;1161:146–151. PubMed

Lorke DE, Hasan MY, Nurulain SM, Sheen R, Kuca K, Petroianu GA. Entry of two new asymmetric bispyridinium oximes (K-27 and K-48) into the rat brain: comparison with obidoxime. J. Appl. Toxicol. 2007;27:482–490. PubMed

Bartosova L, Kuca K, Kunesova G, Jun D. The acute toxicity of the acetylcholinesterase reactivators in mice in relation to their structure. Neurotoxicity Res. 2006;9:291–296. PubMed

Bajgar J. Biological monitoring of exposure to nerve agents. Br. J. Ind. Med. 1992;49:648–653. PubMed PMC

Ellman GL, Coutney DK, Andres V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 1961;7:88–95. PubMed

Pohanka M, Jun D, Kuca K. Improvement of acetylcholinesterase-based assay for organophosphates in way of identification by reactivators. Talanta. 2008;77:451–454. PubMed

Kassa J. Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J. Toxicol. Clin. Toxicol. 2002;40:803–816. PubMed

Acetylcholinesterase reactivators (HI-6, obidoxime, trimedoxime, K027, K075, K127, K203, K282): structural evaluation of human serum albumin binding and absorption kinetics

Effect of seven newly synthesized and currently available oxime cholinesterase reactivators on cyclosarin-intoxicated rats